Mutations in several genes have now been identified to cause a massive and specific reduction in the total number of neurons in the human brain. The specific role of these primary microcephaly (MCPH) genes in neural progenitors has yet to be fully defined. We have found that that the products of these genes, MCPH proteins, are localized to the point of abscission in dividing cells, and we hypothesize that asymmetric cell abscission in neocortical progenitors is regulated by interactions between MCPH proteins. We will pursue this hypothesis by addressing 4 specific aims: 1) Define the complex of microcephaly proteins at the midbody ring during neurogenesis; 2) Examine the role of microcephaly proteins in the timing and location of cell abscissions in neural progenitors; 3) Determine the effects of midbody ring inheritance on subsequent neural progenitor outcomes; 4) Identify mechanisms that link cell abscissions to apical junctions in neocortical neuroepithelium. PUBLIC HEALTH RELEVANCE: Mutations in several genes have now been identified to cause a massive and specific reduction in the total number of neurons in the human brain. The specific role of these primary microcephaly (MCPH) genes in neural progenitors has yet to be fully defined. We have found that that the products of these genes, MCPH proteins, are localized to the point of abscission in dividing cells, and we hypothesize that asymmetric cell abscission in neocortical progenitors is regulated by interactions between MCPH proteins.